Genetic Variant KPNA5:c.1433-21_1433-14dupTATATATA (chr6-116732074-T-TTATATATA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001366306.2(KPNA5):c.1433-21_1433-14dupTATATATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 67,188 control chromosomes in the GnomAD database, including 58 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.018 ( 58 hom., cov: 12)

Exomes 𝑓: 0.0011 ( 0 hom. )

Consequence

KPNA5
NM_001366306.2 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00

Publications

3 publications found

Variant links:

Genes affected

KPNA5 (HGNC:6398): (karyopherin subunit alpha 5) The transport of molecules between the nucleus and the cytoplasm in eukaryotic cells is mediated by the nuclear pore complex (NPC) which consists of 60-100 proteins and is probably 120 million daltons in molecular size. Small molecules (up to 70 kD) can pass through the nuclear pore by nonselective diffusion; larger molecules are transported by an active process. Most nuclear proteins contain short basic amino acid sequences known as nuclear localization signals (NLSs). KPNA5 protein belongs to the importin alpha protein family and is thought to be involved in NLS-dependent protein import into the nucleus. [provided by RefSeq, Jul 2008]

KPNA5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Homozygotes in GnomAd4 at 58 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KPNA5	NM_001366306.2 link	c.1433-21_1433-14dupTATATATA		intron_variant	Intron 13 of 13	ENST00000368564.7	NP_001353235.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KPNA5	ENST00000368564.7 link	c.1433-62_1433-61insTATATATA		intron_variant	Intron 13 of 13	1	NM_001366306.2	ENSP00000357552.1		O15131

Frequencies

GnomAD3 genomes

AF:

0.0183

AC:

847

AN:

46368

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00962

Gnomad AMI

AF:

0.00746

Gnomad AMR

AF:

0.0137

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.0120

Gnomad SAS

AF:

0.00909

Gnomad FIN

AF:

0.00576

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0271

Gnomad OTH

AF:

0.0178

GnomAD4 exome

AF:

0.00110

AC:

AN:

20820

Hom.:

AF XY:

0.000932

AC XY:

AN XY:

11802

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

958

American (AMR)

AF:

0.00139

AC:

AN:

722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

974

East Asian (EAS)

AF:

0.000952

AC:

AN:

1050

South Asian (SAS)

AF:

0.000613

AC:

AN:

1630

European-Finnish (FIN)

AF:

0.00419

AC:

AN:

3580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000460

AC:

AN:

10864

Other (OTH)

AF:

0.00

AC:

AN:

978

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.316

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0182

AC:

846

AN:

46368

Hom.:

Cov.:

AF XY:

0.0157

AC XY:

334

AN XY:

21310

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00961

AC:

139

AN:

14468

American (AMR)

AF:

0.0137

AC:

AN:

4608

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

AN:

1402

East Asian (EAS)

AF:

0.0115

AC:

AN:

1396

South Asian (SAS)

AF:

0.00909

AC:

AN:

1430

European-Finnish (FIN)

AF:

0.00576

AC:

AN:

1042

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0271

AC:

576

AN:

21216

Other (OTH)

AF:

0.0177

AC:

AN:

620

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.372

Heterozygous variant carriers

103

138

172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

BranchPoint Hunter

2.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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6-116732074-TTATATATATATATATATATATATATATATATATATATATATA-TTATATATATATATATATATATATATATATATATATATATATATATATATA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over